The role of nitric oxide in passive leg movement-induced vasodilatation with age: insight from alterations in femoral perfusion pressure

Abstract

The passive leg movement (PLM) model is a novel approach to assess vascular function. Increasing femoral perfusion pressure (FPP) by moving from the supine to the upright-seated posture augments the vasodilatory response to PLM in the young, with no effect in the old, but whether this augmented vasodilatation is nitric oxide (NO) dependent is unknown. Using an intra-arterial infusion of N(G) -monomethyl-L -arginine (L -NMMA) to inhibit nitric oxide synthase (NOS), the posture-induced increases in the PLM responses in the young were nearly ablated, with no effect of NOS inhibition in the old. Therefore, PLM in combination with alterations in posture can be used to determine changes in NO-mediated vasodilatation with age, and thus, may be a clinically useful tool for assessing NO bioavailability across the human lifespan. We sought to better understand the contribution of nitric oxide (NO) to passive leg movement (PLM)-induced vasodilatation with age, with and without a posture-induced increase in femoral perfusion pressure (FPP). PLM was performed in eight young (24 ± 1 years) and eight old (74 ± 3 years) healthy males, with and without NO synthase inhibition via intra-arterial infusion of N(G) -monomethyl-L -arginine (L -NMMA) into the common femoral artery in both the supine and upright-seated posture. Central and peripheral haemodynamic responses were determined second-by-second with finger photoplethysmography and Doppler ultrasound, respectively. PLM-induced increases in heart rate, stroke volume, cardiac output and reductions in mean arterial pressure were similar between age groups and conditions. In the young, L -NMMA attenuated the peak change in leg vascular conductance (ΔLVCpeak ) in both the supine (control: 7.4 ± 0.9; L -NMMA: 5.2 ± 1.1 ml min(-1) mmHg(-1) , P < 0.05) and upright-seated (control: 12.3 ± 2.0; L -NMMA: 6.4 ± 1.0 ml min(-1) mmHg(-1) , P < 0.05) posture, with no significant change in the old (supine control: 4.2 ± 1.3; supine L -NMMA: 3.4 ± 0.8; upright-seated control: 4.5 ± 0.8; upright-seated L -NMMA: 3.4 ± 0.8 ml min(-1) mmHg(-1) , P > 0.05). Increased FPP augmented the ΔLVCpeak in the young control condition only (P < 0.05). In the upright-seated posture, NOS inhibition attenuated the FPP-induced augmentation of rapid vasodilatation in the young (control: 1.25 ± 0.23; L -NMMA: 0.74 ± 0.11 ml min(-1) mmHg(-1) s(-1) ; P < 0.05), but not the old (control: 0.37 ± 0.07; L -NMMA: 0.25 ± 0.07 ml ml min(-1) mmHg(-1) s(-1) ; P > 0.05). These data reveal that greater FPP increases the role of NO in PLM-induced vasodilatation in the young, but not the old, due to reduced NO bioavailability with age. Therefore, PLM involving alterations in posture may be useful to determine changes in NO bioavailability with age.

Figure 1

PLM-induced leg vascular conductance peak change and area under the curve A, leg vascular conductance (LVC, ml min⁻¹ mmHg⁻¹) in both the supine (left) and upright-seated (right) posture in the young (n = 8) and old (n = 8). Baseline (BL) indicates the average of the 60 s just prior to initiation of passive leg movement (PLM). Dashed line at 0 s indicates the start of 2 min of PLM. B, peak change (Δ) in LVC. C, area under the curve (AUC) for LVC. *P < 0.05 significantly different vs. the saline condition, ^#P < 0.05 significantly different vs. the young, ^†P < 0.05 significantly different vs. the supine posture. Data illustrated as means ± SEM.

Figure 2

Contribution of nitric oxide to vasodilatory reserve capacity with age The difference in the PLM-induced peak change in leg vascular conductance (ΔLVC_peak, ml min⁻¹ mmHg⁻¹) between the supine and upright-seated posture (vasodilatory reserve) in the young (n = 8) compared to the old (n = 8) during infusion of saline or _L-NMMA. *P < 0.05 significantly different vs. the saline condition, ^#P < 0.05 significantly different vs. the young. Data illustrated as means ± SEM.

Figure 3

Reductions in the PLM-induced peak change in leg vascular conductance during nitric oxide synthase inhibition The reduction in the PLM-induced peak change in leg vascular conductance (ΔLVC_peak, ml min⁻¹ mmHg⁻¹) due to intra-arterial infusion of _L-NMMA during the supine and upright-seated postures in old (n = 8) and young (n = 8) subjects. ^†P < 0.05 significantly different vs. the supine posture, ^#P < 0.05 significantly different vs. the young. Data illustrated as means ± SEM.

Figure 4

Effects of altered femoral perfusion pressure and age on the contribution of nitric oxide (NO) to PLM-induced rapid vasodilatation The slopes calculated for the increase in the leg vascular conductance (LVC, ml min⁻¹ mmHg⁻¹) over time (7 s) reveal a reduced NO-independent contribution to rapid vasodilatation with age in the supine posture (left). Increased femoral perfusion pressure (FPP) (upright-seated) resulted in a more rapid onset of NO-mediated vasodilatation in the young (n = 8), with no effect in the old (n = 8). *P < 0.05 significantly different vs. the saline condition, ^#P < 0.05 significantly different vs. the young, ^†P < 0.05 significantly different vs. the supine posture. Data illustrated as means ± SEM.